Parkinson's disease is the second most common neurodegenerative disease associated with aging. Mutations in PTEN induced kinase 1 (PINK1) and PARKIN cause autosomal recessive forms and some sporadic cases of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence, whereas PARKIN encodes a putative E3 ubiquitin ligase. Drosophila melanogaster contains single homologs of pink1 and parkin, and the residues mutated in versions of PINK1 and PARKIN associated with human disease are largely conserved in flies. We have previously shown that loss of pink1 in Drosophila results in male sterility, muscle degeneration and stress sensitivity due to defects in mitochondrial morphology and function. Moreover, pink1 and parkin function in the same genetic pathway, with pink1 positively regulating parkin. In addition, expression of human PINK1 in pink1 mutant flies rescues the pink1 mutant phenotypes, suggesting that human and Drosophila pink1 are functionally conserved. We aim to use pink1 and parkin mutations as an entry point to study how pink1 and parkin interact to regulate mitochondrial function, and how dysregulation of this pathway leads to compromised mitochondrial function, which is important in Parkinson's disease pathogenesis. Specifically, we will carry out genetic screens to identify other components of the pink1/parkin pathway, investigate the molecular mechanisms of how pink1 and parkin interact and study the role of a pink1-binding protein. Many neurodegenerative disorders of aging are associated with mitochondrial dysfunction. The identification of new components in pink1/parkin pathway is likely to provide insight in pathogenesis of aging-related neurodegenerative diseases, including Parkinson's disease, and may identify new diagnostic tools and therapeutic targets. Our long-term goal, which may require collaborations with other labs, is to explore functions of pink1/parkin pathway components in mammals and to search for potential mutations in these genes in patients with neurodegenerative diseases particularly Parkinson's disease, and mechanisms by which defects in this pathway can be suppressed. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the second most common aging-dependent neurodegenerative diseases. We have shown that Drosophila homologs of two genes, pink1 and parkin, function in a common pathway to regulate mitochondrial function. The proposal aims to use pink1/parkin as an entry point to study the role of mitochondrial function in regulating age-dependent processes.